- Aromatization of norethindrone in human adult liver
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Homogenates of human adult liver are capable of aromatization norethindrone (17-α-ethynyl-19-nortestosterone) to ethynylestradiol (17α-ethynylestradiol).The evidence of ethynylestradiol formation was obtained using a Boi-Rad AG1-X2 column, thin layer chromatography and co-crystallization.
- Urabe, Mamoru,Yamamoto, Takara,Yishiji, Shuichi,Honjo, Hideo,Okada, Hiroji
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- Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer
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1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.
- Alotaibi, Faez,Halaweish, Fathi,Halaweish, Hossam,Iram, Surtaj,Kasten, Abigail,Kyeremateng, Jennifer,Ostlund, Trevor
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- O-(Aminosulfonylation) of phenols and an example of slow hydrolytic release
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Sequential replacement of imidazole from sulfonyldiimidazole by phenols and then amines leads to O-arylsulfamate esters. Application of this coupling method to 19 phenols and 6 amines generates a library of 114 sulfamate esters, Ar-OSO2-NR2. A sulfamate based conjugate of ethinyl estradiol was prepared by using the steroid 3-hydroxyl as the phenol component, and an amino amide derived from linoleic acid as the amine. Hydrolysis of this conjugate was studied in aqueous buffer at pH values 2, 5, and 7.4, and (essentially identical) respective half-lives of 6.8, 6.6, and 6.7 days were observed.
- Yang, Baocheng,Sun, Zhexun,Liu, Changzhi,Cui, Yan,Guo, Zhilei,Ren, Yuwei,Lu, Zhijian,Knapp, Spencer
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supporting information
p. 6658 - 6661
(2014/12/11)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Microbial transformation of antifertility agents, norethisterone and 17α-ethynylestradiol
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The microbial transformation of oral contraceptive norethisterone (1) by Cephalosporium aphidicola afforded an oxidized metabolite, 17α- ethynylestradiol (2), while the microbial transformation of 2 by Cunninghamella elegans yielded several metabolites, 19-nor-17α-pregna-1,3,5 (1O)-trien-20-yne-3,4,17β-triol (3), 19-nor-17β-pregna-1,3,5 (10)-trien-20-yne-3,7α,17β-triol (4), 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,11α,17β-triol(5), 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,6β,17β-triol (6) and 19-nor-17α-pregna-1,3,5 (10)-trien-20-yne-3,17β-diol-6β-methoxy (7). Metabolite 7 was found to be a new compound. These metabolites were structurally characterized on the basis of spectroscopic techniques.
- Choudhary, Muhammad I.,Musharraf, Syed G.,Ali, Rahat A.,Atif, Muhammad,Atta-ur-Rahman
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p. 319 - 323
(2007/10/03)
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- Pharmaceutical composition with tumor necrosis factor A and 2-methoxyestrone-3-0-sulphamate for inhibition of estrone sulphatase
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A composition is described. The composition comprises i) a compound comprising a sulphamate group (“a sulphamate compound”); and ii) a biological response modifier.
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- Compound
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Disclosed and claimed are compounds suitable for use as an inhibitor of oestrone sulphatase in a subject in need thereof, as well as compositions containing such compounds and methods for using such compounds. Such compounds can be a sulphamate compound that has the Formula (X) and wherein X is a sulphamate group, and Y is CH2 and optionally any other H attached directly to the ring system is substituted by another group
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- Halogenated sulphamate-, phosphonate-, thiophosphonate-, sulphonate- and sulphonamide- compounds as inhibitors of steroid sulphatase
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A compound is described. The compound has the formula (Ia) as presented in the FIG. 1; wherein: X is a ring having at least 4 atoms in the ring; K is hydrocarbyl group; Rh1 is an optional halo group; Rh2 is an optional halo group; at least one of Rh1 and Rh2 is present; Rs is any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group. The compound is capable of inhibiting steroid sulphatase (STS) activity.
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- 17-Aryl linker derivatised estrogen 3-sulphamates as inhibitors of steroid sulphatase
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There is provided a compound comprising a steroidal ring system and a group R1 selected from any one of a sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group; wherein the D ring of the steroidal ring system is substituted by a group R2 of the formula —L—R3, wherein L is an optional linker group and R3 is an aromatic hydrocarbyl group.
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- Use
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There is provided use of a material selected from (i) microtubule stabilizing agent; (ii) microtubule disrupter; (iii) a compound of the formula A-B wherein A is an oxyhydrocarbyl group and B is a cyclic group; and (iv) a compound of the formula C-D wherein C is an sulphamate group and D is a cyclic group, for the manufacture of a medicament for the inhibition of tumor necrosis factor α (TNFα) stimulated aromatase activity.
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- Composition
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There is provided a pharmaceutical composition comprising (i) a compound of the formula wherein: X is a hydrocarbyl ring having at least 4 atoms in the ring; K is a hydrocarbyl group; Rs is a sulphamate group; (ii) optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, wherein the compound is present in an amount to provide a dosage of no greater than 200 μg/day.
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- Composition
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There is provided a pharmaceutical composition comprising (i) a compound of the formula wherein: X is a hydrocarbyl ring having at least 4 atoms in the ring; K is a hydrocarbyl group; Rs is a sulphamate group; (ii) optionally admixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, wherein the compound is present in an amount to provide a dosage of no greater than 200 μg/day.
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- Pharmaceutical combined preparation, kit and method for hormonal contraception
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PCT No. PCT/DE96/01192 Sec. 371 Date Jun. 3, 1998 Sec. 102(e) Date Jun. 3, 1998 PCT Filed Jun. 27, 1996 PCT Pub. No. WO97/01342 PCT Pub. Date Jan. 16, 1997The present invention describes a two-stage pharmaceutical combined preparation for hormonal contraception containing at least 30 daily unit doses, which preparation, in its first stage, comprises as hormonal active ingredient a combination of an oestrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in single stage form and, in the second stage comprises as hormonal active ingredient an oestrogen preparation only, wherein the first stage comprises a minimum of 25 and a maximum of 77 daily discrete or continuous unit doses and the second stage comprises 5, 6 or 7 daily discrete or continuous unit doses, and wherein the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days. This combined preparation, in the form of a monthly pack, which is used for female fertility control, permits as low as possible an oestrogen content in each individual unit dose and also has a low total hormone content per cycle of administration, with high contraceptive reliability, low incidence of follicle development, and satisfactory cycle control with reliable avoidance of intermediate bleeding as well as undesired side effects.
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- STEROID SULPHATASE INHIBITORS
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Steroid sulphatase inhibitors and pharmaceutical compositions containing them for use in the treatment of oestrone dependent tumors, especially breast cancer. The steroid sulphatase inhibitors are sulphonate and phosphonate esters of formula (I), where R is alkyl, alkenyl, cycloalkyl or aryl; X is P or S; Y is OH when X is P, and O when X is S; and -O- polycycle represents the residue of a polycyclic alcohol such as a sterol, preferably a 3-sterol
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- Preparative chemical methods for aromatization of 19-nor-Δ4-3-oxosteroids
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Two preparative chemical methods for aromatization of 19-nor-Δ4-3-oxosteroids are described.The first method consists of an oxidative aromatization of 19-nor-Δ4-3-oxosteroids with iodine-ceric ammonium nitrate in methanol to give a mixture of 3-methoxy ring-A aromatized derivatives consisting of the desired product, the Δ9,11 derivative, the 6-oxo derivative as well as some ring-A iodinated material.Conversion of this material to a mixture of the 3-methoxy ring-A aromatized derivative and its 6-oxo derivative was achieved by catalytic hydrogenation.Finally, reduction of the 6-oxo function with triethylsilane in trifluoroacetic acid gave the 3-methoxy-17-trifluoroacetate ring-A aromatized derivative as a single product.In the second method, reaction of 19-nor-Δ4-3-oxosteroids with copper(II) bromide in acetonitrile at room temperature resulted in aromatic steroids in a single step in excellent yields.The second method was used in the first practical chemical synthesis of a 6-dehydroestrogen from a 19-nor-Δ4,6-3-oxosteroid. - Keywords: copper(II) bromide; ceric ammonium nitrate; iodine; aromatization; 19-nor-Δ4-3-oxosteroids
- Rao, Pemmaraju N.,Cessac, James W.,Kim, Hyun K.
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p. 621 - 627
(2007/10/02)
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- Steroid sulphatase inhibitors
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The present invention provides pharmaceutical preparations for the treatment of estrogen dependent tumors. The pharmaceutical preparations contain an effective amount of a steroid sulphatase inhibitor of the formula: STR1 where R is alkyl, preferably C 1 -C 6 alkyl, and the ring system A B C D is a steroid nucleus selected from the group consisting of oestrone, dehydroepiandrosterone, substituted oestrones and substituted dehydroepiandrosterones or pharmaceutically acceptable salts thereof.
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- On the Structure, Analytics and Stability of Ethinylestradiol Isopropylsulphonate and Steroidal Companion Substances
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By means of TLC and HPLC the authors determined in ethinylestradiol isopropylsulphonate (1; constituent of Deposiston and Turisteron , VEB Jenapharm, Jena, GDR) two steroidal companion substances and other nonsteroidal compounds in a concentration of less than 1 percent.Spectroscopic studies (UV, IR, MS) evidenced that the compounds isolated by preparative layer chromatography display the structure of 17α-ethinyl-6-oxoestra-3,17β-diol-3-isopropylsulphonate (2) and 17α-ethinylestra-3,17β-diol-17β-isopropylsulphonate (3), respectively.The structure of 2 was confirmed by comparison with an authentic sample.Preliminary stability studies on aqueous solutions showed that 1 is an ester which is stable in acid or neutral medium; in alkaline medium, 17α-ethinylestradiol (8) (which is no companion substance of 1) is formed by hydrolysis of 1.
- Goeber, B.,Seiferth, Sylvia,Franke, P.
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- Chromatographic patterns of urinary ethynyl estrogen metabolites in various populations
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Radioactive mestranol (ME) and/or ethinylestradiol (EE) were administered to women in Nigeria, Sri Lanka, and the USA, and the types and patterns of radioactive urinary conjugates examined by Sephadex LH-20 chromatography. There are no differences in the total excretion of urinary radioactivity over 3 days. Consistent geographic differences appear to be present in the proportion of 3-, 17-, and 3,17-glucuronides. If confirmed on larger population samples, these observations may indicate significant geographic differences in the hepatic metabolism of ethinyl estrogens. High performance liquid chromatographic patterns of the urinary aglycone metabolites of ME and EE were examined in a number of women. The separation was accomplished on a Chromegaprep Diol column with a gradient of isopropranol in heptane. Ethinyl estrogen metabolism shows considerable individual variation. EE is usually the principal compound excreted following ME or EE administration. Unmetabolized ME is present in the ME profiles. The profiles of EE and ME are similar, with EE demonstrating a more complex pattern. Oxidative metabolism occurs chiefly at positions 2, 6, and 16 and is fairly extensive in the USA subjects. The Sri Lankan women generally show less of the oxidative products and the Nigerian group display a notable lack of oxidative metabolism. There is no difference in the metabolic patterns of long-term oral contraceptive users vs. non-users. Using silver sulfoethylcellulose column chromatography, from 14.1 to 34.7% of the excreted radiolabeled aglycones are non-ethinyl (i.e. either D-homo or de-ethinylated estrogens). Types and patterns of radioactive urinary conjugates were examined by Sephadex LH-20 chromatography after ingestion of radiolabeled mestranol and/or ethinyl estradiol in a variety of populations. Women in Nigeria, Sri Lanka, and the United States were given the radioactive estrogens. Over 3 days, no differences in total excretion of urinary radioactivity were found. However, there were consistent geographical differences in the proportion of 3-, 17-, and 3,17-glucuronides, indicating significant geographical differences in hepatic metabolism of ethinyl estrogens. Then high-performance liquid chromatographic patterns of urinary aglycone metabolites of mestranol and ethinyl estradiol were studied after successful separation on a Chromegaprep Diol column. Ethinyl estrogen metabolism showed great individual variation. Ethinyl estradiol was the principal compound excreted after ingesting either ethinyl estradiol or mestranol. Unmetabolized mestranol was found as well. Ethinyl estradiol and mestranol profiles were similar, with ethinyl estradiol demonstrating a more complex pattern. U. S. subjects displayed extensive oxidative metabolism (Positions 2, 6, and 16), Sri Lankans less Nigerians very little if any. No difference in metabolic patterns was seen among long-term vs. short-term users vs. nonusers.
- Williams,Goldzieher
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p. 255 - 282
(2007/10/02)
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- 17β-Ethynyl-3,17α-estradiol and derivatives thereof
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17β-ethynyl-3,17α-estradiol and derivatives thereof are prepared by epimerization of 17-acyl esters of 17α-ethynyl-3,17β-estradiol 3-ethers. 17α-ethynyl-3,17α-estradiol and its derivatives are active as post-coital antifertility agents and inhibit the growth of or reduce the size of the prostate gland and the seminal vesicle.
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- Novel N-nitroso compounds, compositions containing such compounds, processes for their preparation and methods of treatment therewith, and novel intermediates
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This invention relates to novel N-halogenoalkyl-N-nitroso carbamates and N 4 halogenalkyl-N 4 -nitroso allophanates of steroid compounds, having an anti-tumor activity, and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and methods of treatment therewith.
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